The applicant proposes two specific aims and each of these has three associated hypotheses. Aim 1. To determine whether endogenous activin stimulates glycoprotein hormone biosynthesis and cell proliferation in human pituitary tumors. Hypotheses: a) Activin specifically stimulates follicle stimulating hormone-beta (FSHb) gene expression and clonal cell proliferation in human tumors. b) preferential FSHb biosynthesis identified in pituitary tumors reflects increased endogenous activin-B expression. c) Inhibin modifies activin effects and decreases FSHb biosynthesis in neoplastic gonadotropes. Aim 2. To investigate novel somatic mutations and pathogenetic mechanisms in human pituitary tumors. Hypotheses: a) glycoprotein hormone subunit gene rearrangements occur in a subset of human pituitary tumors. b) alpha-subunit hypersecretion and regulation in pleurihormonal somatotroph tumors identifies somatotroph adenomas in which G-protein mutations occur. c) Ras mutations can be identified in specific pituitary tumor phenotypes.